Epidrugs: targeting epigenetic marks in cancer treatment

Abstract

Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of cancer. Unlike genetic mutations, the ability to reprogram the epigenetic landscape in the cancer epigenome is one of the most promising target therapies in both treatment and reversibility of drug resistance. Epigenetic alterations in cancer development and progression may be the basis for the individual variation in drug response. Thus, this review focuses on the emerging area of pharmaco(epi)genomics, specifically highlighting epigenetic reprogramming during tumorigenesis and how epigenetic markers are targeted as a therapy (epidrugs) and the clinical implications of this for cancer treatment.

Keywords: Epigenetics; cancer; epidrugs; pharmacology; reprogramming; treatment.

Figure 1.

Schematic representation of epigenetic modifications and epidrugs action. The modification of cytosine to 5-methylcytosine (5mC) DNA methylation is catalyzed by DNA methyltransferases (DNMTs). DNMTs require S-Adenosylmethionine (SAM) as a cofactor for methyl group donation that is converted to S-adenosylhomocysteine (SAH). DNA methylation at a promoter region is related to transcriptional silencing. The DNMT inhibitors (DNMTi) block DNA methylation and restore the function of aberrantly silenced genes. At the chromatin level, histone post-translational acetylation is catalyzed by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs). Such modifications occur into amino acid residues (such as lysine) at histone tails. HDAC inhibitors (HDACi) induce the acetylation, an epigenetic modification associated with transcriptional activation and gene expression

Figure 2.

Progress of epigenetic drugs in different stages of pharmacological studies. The number of epigenetic studies from 2009 to 2019 according to ‘web of science’ database is showed according to each study phase: in vitro (1217) in vivo (952), preclinical (465) and clinical (137). The map represents the global distribution of clinical epigenetic drug studies according to clinical trial database (www.clinicaltrial.org, june, 2019), and the box show the exact number of studies.